Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same

ABSTRACT

Novel analgesic and anti-inflammatory compositions of matter for use in eliciting an analgesic or anit-inflammatory response, said compositions comprising caffeine together with a selected non-narcotic analgesic/nonsteroidal anti-inflammatory drug or a selected narcotic analgesic, or both, are disclosed. When used in combination with the selected drugs, caffeine enhances the analgesic or anti-inflammatory response and also hastens its onset.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of Ser. No. 643,196, filed Aug. 22, 1984,now U.S. Pat. No. 4,587,249, which is a division of Ser. No. 474,358,filed Mar. 11, 1983, now U.S. Pat. No. 4,486,436, which is acontinuation of Ser. No. 400,597, filed July 22, 1982, now abandoned.

The subject matter of this application is related to that of our patentapplications entitled "IMPROVED ANALGESIC COMPOSITIONS COMPRISINGPROPIRAM AND METHODS OF USING SAME" Ser. No. 488,815 filed 4-26-83, nowU.S. Pat. No. 4,479,956 and IMPROVED ANALGESIC AND ANTI-INFLAMMATORYCOMPOSITIONS COMPRISING IBUPROFEN AND METHODS OF USING SAME" Ser. No.400,645, filed 7-22-82 now U.S. Pat. No. 4,420,483, both incorporated byreference herein and relied upon.

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical compositions ofmatter comprising caffeine and one or more analgesic agents, or caffeineand an anti-inflammatory agent, and to methods of using saidcompositions to hasten the onset of an analgesic or anti-inflammatoryresponse and to enhance an analgesic or anti-inflammatory response.

BACKGROUND ART

Non-narcotic analgesics, most of which are also known as non-steroidalanti-inflammatory drugs (NSAID), are widely administered orally in thetreatment of mild to severe pain. Within this class, the compounds varywidely in their chemical structure and in their biological profiles asanalgesics, anti-inflammatory agents and antipyretic agents. Aspirin,acetaminophen and phenacetin have long been among the most commonly usedmembers of this group; more recently, however, a large number ofalternative non-narcotic agents offering a variety of advantages overthe earlier drugs have been developed. Tolerance or addiction to thesedrugs is not generally a problem with their continuous use in thetreatment of pain or in the treatment of acute or chronic inflammatorystates (notably, rheumatoid arthritis and osteoarthritis); nevertheless,these drugs generally have a higher potential for adverse side-effectsat the upper limits of their effective dose ranges. Moreover, above eachdrugs's upper limit or ceiling, administration of additional drug doesnot usually increase the analgesic or anti-inflammatory effect. Amongthe newer compounds in the non-narcotic analgesic/nonsteroidalanti-inflammatory group are compounds such as diflunisal (Dolobid®),zomepirac sodium (Zomax®), ibuprofen (Motrin®), naproxen (Naprosyn®),fenoprofen (Nalfon®), piroxicam (Feldene®), flurbiprofen, mefenamic acid(Ponstel®) and sulindac. See also Physician's Desk Reference, 35thedition, 1981, and The Merck Index, ninth edition, Merck & Co., Rahway,N.J. (1976), for information on specific nonsteroidal anti-inflammatoryagents. Also see, generally, Wiseman, "Pharmacological Studies with aNew Class of Nonsteroidal Anti-Inflammatory Agents--The Oxicams--WithSpecial Reference to Piroxicam (Feldene®), The American Journal ofMedicine, Feb. 16, 1982: 2-8; Foley et al, The Management of CancerPain, Volume II--The Rational Use of Analgesics in the Management ofCancer Pain, Hoffman-LaRoche Inc., 1981; and Cutting's Handbook ofPharmacology, sixth edition, ed. T. Z. Czaky, M.D.,Appleton-Century-Crofts, New York, 1079, Chapter 49: 538-550.

Narcotic analgesics are often used when pain control with non-narcoticanalgesics is ineffective. While the drugs in this group varyconsiderably in their chemical structures and pharmacologicalproperties, almost all suffer the disadvantages of tolerance andpossible addiction with continued usage. Within the narcotic analgesicgroup, the drugs can be classified as narcotic agonists or narcoticantagonists. Narcotic agonists include the morphine group, themeperidine group and the methadone group. While some narcoticantagonists are pure antagonists (which are not analgesics), othernarcotic antagonists are agonist-antagonists (i.e. antagonists withanalgesic properties); the agonist-antagonists are generally categorizedas morphine-like or nalorphine-like). Many of the narcotic analgesicsare not effective orally, but are rather used parenterally. The orallyactive narcotic analgesics include such compounds as codeine, oxycodone,levorphanol (Levo-Dromoran®), meperidine (Demerol®), propoxyphenehydrochloride (Darvon®), propoxyphene napsylate (Darvon-N®), methadone,propiram, buprenorphine, pentazocine (Talwin®), nalbuphine (Nubain®) andbutorphanol (Stadol®). For more specific information on these compounds,see Physicians' Desk Reference, 35th edition, 1981, and The Merck Index,ninth edition, Merck & Co., Inc., Rahway, N.J (1976). Also see,generally, the Foley et al reference cited hereinabove and Cutting'sHandbook of Pharmacology, sixth edition, ed. T. Z. Czaky, M.D.,Appleton-Century-Crofts, New York, 1979, Chapter 50: 551-566.

Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, has thestructural formula ##STR1## This substance has been used alone,intravenously, in the treatment of headaches and has also been used incombination with selected drugs. Compositions containing one or more ofthe analgesics aspirin, acetaminophen and phenacetin in combination withvarying amounts of caffeine have been marketed in the past; in severalcases, such non-narcotic analgesic/caffeine combination products havefurther included one of the narcotic analgesics codeine, propoxyphene oroxycodone. Examples of these combinations include the products knowncommercially as Excedrin®, SK-65® Compound, Darvon® Compound, Anacin®,A.P.C., and A.P.C. with Codeine, Tabloid® Brand. The nonsteroidalanalgesic components of these mixtures have the following structuralformulas: ##STR2##

The three narcotic analgesics which have occasionally been added to theaspirin/phenacetin/acetaminophen/caffeine combinations have thefollowing structural formulas: ##STR3## As far as the present inventorsknow, however, the art has never suggested that caffeine be added to anarcotic analgesic to contribute to its analgesic effect.

Many workers have sought to demonstrate the efficacy of theaspirin/phenacetin/acetaminophen/caffeine combination products. Anextensive review of the literature on caffeine and analgesics has beenpublished ["Over-The-Counter Drugs: Establishment of a Monograph for OTCInternal Analgesic, Antipyretic and Antirheumatic Products," FederalRegister, 1977, 42 (131): 35482-35485] and several relevant additionalarticles have appeared. Most animal studies on caffeine analgesia havebeen performed on the rat. Williams (Toxicology and AppliedPharmacology, 1959, 1: 447-453) utilized experimental pain and foundthat caffeine alone exerted analgesic effects on rats and when combinedwith aspirin; the effect appeared additive but not potentiating. Vinegaret al. (Proceedings of the Society for Experimental Biology andMedicine, 1976, 151: 556-560), ten years later, found that in the ratcaffeine potentiates the acute anti-inflammatory and analgesic activityof aspirin. Siegers (Pharmacology, 1973, 10: 19-27) studied the effectof oral doses of caffeine (10, 50 and 100 mg/kg) given to rats togetherwith acetaminophen and found that caffeine inhibited its absorption andlowered its serum concentration. He suggested that delayed stomachemptying as a result of the relaxing effect of caffeine on gastricsmooth muscle was probably the cause of the diminished absorption oforally administered drugs in the presence of caffeine. Despite thisfinding, acetaminophen analgesia was not decreased by caffeine. Inagreement with Williams and Vinegar and his associates, Siegers foundthat caffeine itself had analgesic activity. Only in the lowest dose ofcaffeine studied, a dose at which analgesia was not exhibited, was therea reduction in the acetaminophen induced analgesia. In a more recentpaper, Seegers et al (Arch. Int. Pharmacodyn., 1981, 251: 237-254)demonstrated an anti-inflammatory, analgesic effect of caffeine in rats.He also found that the combination of caffeine, aspirin andacetaminophen as well as the combination of caffeine, aspirin andphenacetin at low doses produced anti-inflammatory, analgesic effectswhich are at least as great as would be expected on the basis ofaddition, while at high doses, the results suggested potentiation.Citing the work of Giertz and Jurna (Naturwissenschaften, 1957, 44:445), and Fuchs and Giertz (Arzneimittelforsch, 1960, 10: 526-530), whoobserved that caffeine induced analgesia in assays in mice in whichinflammation was not involved, Seegers asserted that, "it seems safe toassume that the analgesic activity of caffeine consists of at least twocomponents, one independent of and another one dependent on itsanti-inflammatory activity."

The earliest relevant study in humans was reported by Wallenstein(Proceedings of the aspirin symposium, held at the Royal College ofSurgeons, London, 1975). Two tablets of a combination in which eachtablet contained aspirin 210 mg, acetaminophen 150 mg and caffeine 30mg, clearly and significantly produced more analgesia than thecombination without caffeine. The one tablet dose of the combination hadhigher mean scores than either component alone, but was not superior tothe combination without caffeine. Wallenstein speculated that, "dosagemay be an important factor, and caffeine may simply be ineffective muchbelow the 60 mg dose". Booy (Nederlands Tijdschrift Voor Tandheelkinde,1972, 79: 69-75) studied pain relief on each of two days after toothextraction. Patients who reported "great pain" on the first day obtainedmore pain relief from 1000 mg of acetaminophen plus 100 mg of caffeinethan from 1000 mg of acetaminophen alone. On the second day thisdifference was not found, although on both days all treatments weresuperior to placebo. Lim et al (Clin. Pharmacol. Ther., 1967, 8:521-542), reporting a study in which experimental pain was induced inthe subjects by bradykinin, observed that the combination of aspirin 520mg and acetaminophen 260 mg given orally could not be distinguished fromplacebo, whereas the same combination in lesser quantities, aspirin 325mg and acetaminophen 162.5 mg plus caffeine 32.5 mg was significantlydifferent from placebo at 15, 60, 75, 105, and 120 minutes after takingthe drug. A double-blind, crossover study of 216 patients by Wojcicki etal [Archivum Immunologiae et Therapeae Experimentalis, 1977, 25(2):175-179] compared the activity of 1000 mg of acetaminophen plus 100 mgof caffeine against the same quantity of acetaminophen alone. One groupof patients in the trial were suffering severe and frequently occurringidiopathic headache and a second group had moderate post-operativeorthopedic pain. The authors concluded that the relief of pain was fargreater with the caffeine combination than with acetaminophen alone orwith aspirin alone. Jain et al (Clin. Pharmacol. Ther., 1978, 24: 69-75)first studied 70 postpartum patients with moderate to severe uterinecramp and/or episiotomy pain and then a second group of 70 patientslimited to severe pain only. Comparing 800 mg aspirin plus 64 mg ofcaffeine to 650 mg aspirin alone, these authors concluded that inpatients with severe episiotomy pain the combination is the moreeffective analgesic.

Caffeine use in the treatment of headache has a long history. The FDAAdvisory Panel, in its review of caffeine [Federal Register, 1977, 42(131): 35482-35485] argued that the known biochemical effect of caffeineon small blood vessels provides a plausible explanation for itseffectiveness in treating headache associated with cerebral bloodvessels. Recently Sechzer [Curr. Therapy Research, 1979, 26(4)] foundthat the intravenous administration of caffeine sodium benzoate rapidlyprovided relief in the majority of patients experiencing headacheresulting from dural puncture or spinal anesthesia. The author,referring to the literature on the mechanism of action of caffeine oncerebral blood flow and on cerebral vascular tone, argues from theopposite perspective of the Panel that the analgesic relief obtainedimplies that an intracranial vascular component is the primary factor insuch headaches.

Changes in mood and over-all sense of "well-being" after administrationof caffeine have been widely reported in the literature. Beginning inthe early part of this century, Hollingsworth (Arch. Psychol., 1912,22: 1) reported beneficial motor and mental effects from 65 to 130 mg ofcaffeine, and tremor, poor motor performance, and insomnia caused by 390mg of caffeine. Many studies over the past 70 years have confirmed thosefindings. Review articles on the xanthines [Ritchie, J. M., "Centralnervous system stimulants. 2. The xanthines," Goodman, L. S. & Gilman,A. (Eds.), The pharmacological basis of therapeutics, 4th Ed., New York:Macmillan Co., 1970; Stephenson, P. E., "Physiologic and psychotropiceffects of caffeine on man," J. Amer. Diet. Assoc., 1977, 71(3):240-247] report that doses of 50 to 200 mg of caffeine result inincreased alertness, decreased drowsiness, and lessened fatigue. Dosesin the range of 200 to 500 mg may produce headaches, tremor, nervousnessand irritability.

After extensively reviewing the relevant literature, the mostsignificant contributions of which are summarized above, the FDAAdvisory Panel in 1977 concluded that caffeine when used as an analgesicadjuvant was safe, but that there was insufficient data to demonstratethat caffeine contributes anything to the action of the analgesic[Federal Register, 1977, 42 (131): 35482-35485]. The Panel stated:

Unfortunately, the information and data submitted, fail to demonstrateconclusively that caffeine in combination is effective as an analgesic,antipyretic and/or antirheumatic ingredient. The Panel finds there islittle evidence to show that this ingredient even contributes to thesepharmacological effects in the clinical situation.

This remains the official position on the question up to the presenttime. Consequently, many of the analgesic/caffeine combination productspreviously available are no longer on the market.

In addition to the few prior art instances of selected non-narcoticanalgesic/caffeine combinations further containing a selected narcoticanalgesic (which three-component combinations have already beendiscussed hereinabove), there also are examples in the art oftwo-component combinations of selected non-narcotic analgesics withselected narcotic analgesics. Known combinations of this type includeDarvon® with A.S.A.® (propoxyphene hydrochloride and aspirin), Darvon-N®with A.S.A.® (propoxyphene napsylate and aspirin), aspirin with codeine,Talwin® Compound (pentazocine hydrochloride, oxycodone and aspirin),Percodan® (oxycodone hydrochloride, terephthalate and aspirin) andnalbuphine with acetaminophen, the last-mentioned combination beingdisclosed in U.S. Pat. No. 4,237,140. The general principle of use of acombination of drugs to produce additive analgesic effects is known tothose skilled in the art; for example, Foley et al, The Management ofCancer Pain, Volume II--The Rational Use of Analgesics in the Managementof Cancer Pain, Hoffman-LaRoche Inc., 1981, suggest such combination andspecifically point out that 650 mg aspirin or acetaminophen regularlyadded to the standard narcotic dose will often enhance the analgesiceffect without requiring higher doses of the narcotic. Such additiveeffects have been reported earlier by Houde et al, Clin. Pharm. Ther.1(2): 163-174(1960) for intramuscularly administered morphine sulfategiven with orally administered aspirin. As far as the present inventorsknow, however, the art does not suggest any two-component compositionsof a narcotic analgesic and caffeine; it also does not suggest anyimprovements in the analgesic response to be derived fromco-administering caffeine with any narcotic analgesic.

SUMMARY OF THE INVENTION

Surprisingly, the present inventors now find that selected non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs, which differsubstantially in chemical structure from aspirin, phenacetin andacetaminophen, and which have significantly different biologicalprofiles therefrom, can be advantageously formulated into novelpharmaceutical compositions together with caffeine and administered tomammals, especially humans, to not only elicit a more potent analgesicor anti-inflammatory response but also to evoke such response morerapidly than possible by administration of the analgesic oranti-inflammatory agent alone.

The present inventors also find, quite surprisingly, that orallyeffective narcotic analgesics (i.e. narcotic agonists and narcoticagonist-antagonists which are effective orally as analgesics) canlikewise be advantageously formulated into novel pharmaceuticalcompositions together with caffeine and administered to mammals,especially humans, to not only elicit a more potent analgesic responsebut also to evoke such response more rapidly than possible byadministration of the narcotic drug alone. The present inventors furtherfind that orally effective narcotic analgesics can be advantageouslycombined with non-narcotic analgesics and caffeine to form novelpharmaceutical compositions which can be administered to mammals,especially humans, to elicit an improved analgesic response.

In one aspect, the present invention thus provides a novelpharmaceutical composition of matter for use in eliciting an analgesicor anti-inflammatory response, said composition comprising an effectiveanalgesic or anti-inflammatory amount of a selected non-narcoticanalgesic/nonsteroidal anti-inflammatory drug as defined hereinafter andan amount of caffeine sufficient to hasten the onset of the analgesic oranti-inflammatory response or to enhance the analgesic oranti-inflammatory response.

In another aspect, the present invention provides a novel pharmaceuticalcomposition of matter for use in eliciting an analgesic response, saidcomposition comprising an effective analgesic amount of an orallyanalgesically active narcotic agonist or agonist-antagonist and anamount of caffeine sufficient to hasten the onset of the analgesicresponse or to enhance the analgesic response.

In another aspect, the present invention proves a novel pharmaceuticalcomposition of matter for use in eliciting an analgesic response, saidcomposition comprising an effective analgesic amount of an orallyanalgesically active narcotic agonist or agonist-antagonist, an amountof a selected non-narcotic analgesic as defined hereinafter sufficientto enhance analgesia, and an amount of caffeine sufficient to furtherenhance analgesia or to hasten its onset.

Typically, the active ingredients of the compositions of the inventionare further associated with a nontoxic pharmaceutically acceptable inertcarrier therefor.

In other aspects, the invention provides methods of hastening the onsetof an analgesic or anti-inflammatory response and methods of elicitingan enhanced analgesic or anti-inflammatory response in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

The non-narcotic analgesics/nonsteroidal anti-inflammatory drugs for usein the compositions and methods of the present invention can be selectedfrom the following categories:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams.

While some of these compounds are primarily used at the present time asanti-inflammatory agents and others are primarily used as analgesics, infact all of the contemplated compounds have both analgesic andanti-inflammatory activity and can be used at appropriate dosage levelsfor either purpose in the compositions and methods of the presentinvention. The compounds in groups (1) through (4) typically contain acarboxylic acid function; however, those acids are sometimesadministered in the form of their pharmaceutically acceptable salts,e.g. sodium salts.

The propionic acid derivatives for use herein include, but are notlimited to, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen,fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,tiaprofenic acid, fluprofen and bucloxic acid. Structurally relatedpropionic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Presently preferred members of the propionic acid group includeibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen and fenbufen.Structural formulas for representative group members are set forthbelow:

    ______________________________________                                        PROPIONIC ACID DERIVATIVES                                                    ______________________________________                                        ibuprofen                                                                               ##STR4##                                                            naproxen                                                                                ##STR5##                                                            flurbiprofen                                                                            ##STR6##                                                            fenbufen                                                                                ##STR7##                                                            fenoprofen                                                                              ##STR8##                                                            ibuprofen aluminum                                                                      ##STR9##                                                            indoprofen                                                                              ##STR10##                                                           ketoprofen                                                                              ##STR11##                                                           fluprofen                                                                               ##STR12##                                                           bucloxic acid                                                                           ##STR13##                                                           ______________________________________                                    

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g. --CH(CH₃)COO⁻ Na⁺or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via a carbonylfunction to a ring system, preferably to an aromatic ring system.

The acetic acid derivatives for use herein include, but are not limitedto, indomethacin, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac and oxpinac. Structurallyrelated acetic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Presently preferred members of the acetic acid group includetolmetin sodium, zomepirac sodium, sulindac and indomethacin. Structuralformulas for representative group members are set forth below:

    ______________________________________                                        ACETIC ACID DERIVATIVES                                                       ______________________________________                                        zomepirac                                                                               ##STR14##                                                           tolmetin                                                                                ##STR15##                                                           sulindac                                                                                ##STR16##                                                           indomethacin                                                                            ##STR17##                                                           diclofenac                                                                              ##STR18##                                                           alclofenac                                                                              ##STR19##                                                           fenclozic acid                                                                          ##STR20##                                                           ibufenac                                                                                ##STR21##                                                           ______________________________________                                    

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives for use herein include, but are not limitedto, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acidand tolfenamic acid. Structurally related fenamic acid derivativeshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group. Presently preferred members ofthe fenamic acid group include mefenamic acid and meclofenamate sodium(meclofenamic acid, sodium salt). Structural formulas for representativegroup members are set forth below:

    ______________________________________                                        FENAMIC ACID DERIVATIVES                                                      ______________________________________                                        mefenamic acid                                                                               ##STR22##                                                      meclofenamic acid                                                                            ##STR23##                                                      flufenamic acid                                                                              ##STR24##                                                      ______________________________________                                    

Thus, "fenamic acid derivatives" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs which contain the basicstructure ##STR25## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g. --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives for use herein includes, but arenot limited to, diflunisal and flufenisal. Structurally relatedbiphenylcarboxylic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Preferred members of this group are diflunisal and flufenisal,whose structural formulas are set forth below:

    ______________________________________                                        BIPHENYLCARBOXYLIC ACID DERIVATIVES                                           ______________________________________                                        diflunisal                                                                                 ##STR26##                                                        flufenisal                                                                                 ##STR27##                                                        ______________________________________                                    

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/nonsteroidal anti-inflammatory drugs whichcontain the basic structure ##STR28## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g. --COO⁻ Na⁺.

The oxicams for use herein include, but are not limited to, piroxicam,sudoxicam, isoxicam and CP-14,304. Structurally related oxicams havingsimilar analgesic and anti-inflammatory properties are also intended tobe encompassed by this group. A preferred member of this group ispiroxicam; representative members are depicted below:

    ______________________________________                                        OXICAMS                                                                       ______________________________________                                        piroxicam                                                                                ##STR29##                                                          sudoxicam                                                                                ##STR30##                                                          isoxicam                                                                                 ##STR31##                                                          CP-14,304 (4-hydroxy-1,2- benzothiazine 1,1-dioxide 4- (Nphenyl)-             carboxamide]                                                                             ##STR32##                                                          ______________________________________                                    

Thus, "oxicams" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs which have the generalformula ##STR33## wherein R is an aryl or heteroaryl ring system.

The narcotic analgesics for use in the present invention are orallyactive narcotic agonists and narcotic agonist-antagonists (i.e.antagonists with analgesic properties). Suitable narcotic agonists foruse herein include orally analgesically active members of the morphinegroup, the meperidine group and the methadone group, notably codeine,oxycodone, hydromorphone, levorphanol, meperidine, propoxyphene andmethadone. Suitable agonist-antagonists for use herein include orallyanalgesically active antagonists of the morphine type, notably propiramand buprenorphine; and orally analgesically active antagonists of thenalorphine type, notably pentazocine, nalbuphine and butorphanol.Another suitable agonist-antagonist is meptazinol. In many instances,the narcotic analgesics for use herein are administered in the form oftheir pharmaceutically acceptable acid addition salts, e.g. codeinesulfate, codeine phosphate, oxycodone hydrochloride, oxycodoneterephthalate, hydromorphone hydrochloride, levorphanol tartrate,meperidine hydrochloride, propoxyphene hydrochloride, propoxyphenenapsylate, methadone hydrochloride, propiram fumarate, buprenorphinehydrochloride, nalbuphine hydrochloride and meptazinol hydrochloride.Structural formulas for representative free bases are shown below:

    ______________________________________                                        codeine                                                                                  ##STR34##                                                          oxycodone                                                                                ##STR35##                                                          levorphanol                                                                              ##STR36##                                                          meperidine                                                                               ##STR37##                                                          methadone                                                                                ##STR38##                                                          meptazinol                                                                               ##STR39##                                                          propoxyphene                                                                             ##STR40##                                                          propiram                                                                                 ##STR41##                                                          buprenorphine                                                                            ##STR42##                                                          pentazocine                                                                              ##STR43##                                                          nalbuphine                                                                               ##STR44##                                                          butorphanol                                                                              ##STR45##                                                          hydromorphone                                                                            ##STR46##                                                          ______________________________________                                    

The term "caffeine" as used herein is intended to encompass not onlycaffeine as the anhydrous powder, but any salt or derivative of caffeineor any compounded mixture thereof which is non-toxic, pharmaceuticallyacceptable and which is capable of hastening and enhancing an analgesicor anti-inflammatory response when employed as described herein. See,for example, The Merck Index, ninth edition, Merck & Co., Inc. Rahway,N.J. (1976), pp. 207-208, for a description of caffeine salts,derivatives and mixtures which may prove useful in the compositions ofthe present invention. Nevertheless, caffeine as the anhydrous powderbase is presently preferred and, where specific amounts of caffeine areset forth below, such amounts are given in mg of the anhydrous base.

The term "selected NSAID" as used herein is intended to mean anynon-narcotic analgesic/nonsteroidal anti-inflammatory compound fallingwithin one of the five structural categories indicated hereinabove.Similarly, the term "selected narcotic analgesic" as used herein isintended to mean any orally analgesically active narcotic analgesic, beit an orally active narcotic agonist or a narcotic antagonist havingoral analgesic activity. The terms "selected NSAID" and "selectednarcotic analgesic" are used for the sake of simplicity in thediscussion which follows.

When a selected NSAID is combined with caffeine in accord with thepresent invention, the following unexpected results are produced:

(1) the analgesic or anti-inflammatory effect of the selected NSAID onthe mammal is brought on more quickly;

(2) lower amounts of the selected NSAID are required for the sameanalgesic or anti-inflammatory effect; and

(3) across all doses, a greater analgesic or anti-inflammatory responseis achieved.

For patients suffering pain, the time from administration of medicationto the onset of effective relief is clearly of paramount importance. Thepresent inventors' discovery that caffeine substantially shortens theonset time (i.e. substantially hastens the onset) of analgesia istherefore very significant; moreover, it is completely unexpected.Likewise, in patients suffering inflammation, e.g. from rheumatoidarthritis or osteoarthritis, the substantial shortening of onset timeprovided by this invention is extremely important, not only because itprovides faster relief from pain but also because provides more rapidrelief from other aspects of the inflammatory disease, e.g. morningstiffness.

Further, the ability of caffeine to enhance analgesia or to enhance theanti-inflammatory response, i.e. to substantially reduce the amount ofthe selected NSAID which is required to elicit a given analgesic oranti-inflammatory response, is also an unexpected and very importantaspect of this invention. This unexpected and important finding permitsthe use of the selected NSAID in quantities substantially less than thedosages presently suggested as an analgesic or anti-inflammatory agentin humans. Use of lower doses should in turn lower the incidence and/orseverity of undesirable side effects. Moreover, at a given dosage level,a greater analgesic or anti-inflammatory response can be achieved.

More specifically, it is believed that onset time for analgesia or forthe anti-inflammatory response can be reached, on the average, aboutone-fourth to about one-third sooner when a composition of the inventionis used rather than when the selected NSAID alone is employed. Also,approximately one-fifth to one-third less of the selected NSAID can beused in the caffeine combination to achieve the same analgesic oranti-inflammatory effect as that obtained by use of the selected NSAIDalone; in other words, the addition of caffeine decreases the amount ofthe selected NSAID to about two-thirds to four-fifths of the usualamount to achieve the same effect. These ratios may vary, however,depending on the patient's individual response, the selected dosagelevel of the active ingredients etc.

The precise amount of non-narcotic analgesic/nonsteroidalanti-inflammatory drug for use in the present compositions will varydepending, for example, on the specific drug chosen, the condition forwhich the drug is administered and the size and kind of the mammal.Generally speaking, the selected NSAID can be employed in any amountknown to be an effective analgesic or anti-inflammatory amount, as wellas at doses one-fifth to one-third lower than the usual amounts.

For humans, typical effective analgesic amounts of presently preferredNSAIDs for use in unit dose compositions of the invention are about 125to 500 mg diflunisal, about 25 to 100 mg zomepirac sodium, about 50 to400 mg ibuprofen, about 125 to 500 mg naproxen, about 25 to 50 mgflurbiprofen, about 50 to 200 mg fenoprofen, about 10 to 20 mgpiroxicam, about 125 to 250 mg mefenamic acid, about 100 to 400 mgfenbufen or about 25 to 50 mg ketoprofen; however, greater amounts canbe employed if desired. The amount of caffeine in the analgesiccomposition will be an amount sufficient to shorten the onset timeand/or to enhance analgesia. For humans, a unit dosage analgesiccomposition will typically contain from about 60 to about 200 mg(preferably about 65 to about 150 mg) caffeine; this dosage level ofcaffeine is generally sufficient to both shorten the onset time andenhance analgesia. However, certain NSAIDs are particularly long-actingand need be administered less frequently than the usual every 4 to 6hours; for example, diflunisal and naproxen are typically administeredonly twice daily and piroxicam only once a day. When such long-actingdrugs are employed, it is often desirable to include an additional andanalgesia-enhancing amount of caffeine in the composition in sustainedrelease form; thus, the composition will typically contain from about 60to about 200 (preferably about 65 to about 150) mg caffeine forimmediate release to hasten onset and enhance analgesia, and one (orpossibly more) additional 60 to 200 (preferably 65 to 150) mg dose(s) ofcaffeine for sustained release to continue enhancement of analgesia. Thedaily analgesic dose in humans will vary with the selected NSAID, andmay of course be as low as the amount contained in a single unit dose asset forth above. The daily dose for use in the treatment of mild tomoderate pain will preferably not exceed 1500 mg diflunisal or 600 mgzomepirac sodium or 2400 mg ibuprofen or 1000 mg naproxen or 150 mgflurbiprofen or 2400 mg fenoprofen or 20 mg piroxicam or 1000 mgmefenamic acid or 2400 mg fenbufen or 300 mg ketoprofen, plus 1000 mgcaffeine, for use in the treatment of mild to moderate pain, althoughgreater amounts could be employed if tolerated by the patient.

For humans, typical effective anti-inflammatory amounts of presentlypreferred NSAIDs for use in unit dose compositions of the invention areabout 10 to 20 mg piroxicam, about 250 to 500 mg diflunisal, about 25 to50 mg indomethacin, about 150 to 200 mg sulindac, about 200 to 400 mgtolmetin sodium, about 50 mg meclofenamate sodium, about 65 to 600 mgibuprofen, about 250 to 500 mg naproxen, about 800 to 1200 mg fenbufen,about 50 to 100 mg ketoprofen, or about 200 to 600 mg fenoprofen;however, greater amounts can be employed if desired. The amount ofcaffeine in the anti-inflammatory composition will be an amountsufficient to shorten the onset time and/or to enhance theanti-inflammatory response. For humans, a unit dosage anti-inflammatorycomposition will typically contain from about 60 to 200 mg (preferably65 to 150 mg) caffeine; this dosage level is generally sufficient toboth shorten the onset time and enhance the anti-inflammatory response.Again, the long-acting NSAIDs, i.e. those administered less often than 3or 4 times a day in the treatment of inflammation (e.g. piroxicam,diflunisal, sulindac, tolmetin sodium and naproxen) can be formulatedwith larger amounts of caffeine in the dosage unit, a portion of thecaffeine being in sustained release form. Such compositions willtypically contain from about 60 to 200 (preferably about 65 to 150) mgcaffeine for immediate release to hasten onset and enhance theanti-inflammatory response and one or more additional 60 to 200(preferably 65 to 150) mg doses of caffeine for sustained release tocontinue enhancement of the anti-inflammatory response. The dailyanti-inflammatory dose in humans will vary with the selected NSAID; forexample, the daily dose for use in the treatment of inflammatoryconditions, e.g. rheumatoid arthritis, osteoarthritis and degenerativejoint disease, will generally be about 10 to 20 mg piroxicam, about 250to 1500 mg diflunisal, about 75 to 200 mg indomethacin, about 200 to 600mg sulindac, about 600 to 2000 mg tolmetin sodium, about 200 to 400 mgmeclofenamate sodium, about 1600 to 3000 mg ibuprofen, about 250 to 1000mg naproxen, about 3200 to 4800 mg fenbufen, about 150 to 400 mgketoprofen, or about 1600 to 2400 mg fenoprofen, plus 1000 mg caffeine,although greater amounts could be employed if tolerated by the patient.

When a selected narcotic analgesic is combined with caffeine in accordwith the present invention, the following unexpected results areproduced:

(1) the analgesic effect of the selected narcotic analgesic is broughton more quickly;

(2) lower amounts of the selected narcotic analgesic are required forthe same analgesic effect; and

(3) across all doses, a greater analgesic response is achieved.

For patients suffering pain, and most especially for patients sufferingsevere pain, the time from administration of medication to the onset ofeffective relief is clearly of paramount importance. The presentinventors' discovery that caffeine substantially shortens the onsettime, (i.e. substantially hastens the onset) of analgesia when it iscombined with a selected narcotic analgesic is therefore highlysignificant; moreover, it is totally unexpected.

Further, the ability of caffeine to enhance analgesia, i.e. tosubstantially reduce the amount of selected narcotic analgesic which isrequired to elicit a given analgesic response, is also an unexpected andvery important aspect of this invention. This unexpected and importantfinding permits the use of the selected narcotic analgesic in quantitiessubstantially less than the dosages presently suggested as an analgesicagent in humans. Use of lower doses should in turn lower the incidenceand/or severity of undesirable side effects, including lesseningaddiction potential. Moreover, at a given dosage level, a greateranalgesic response can be achieved.

More specifically, it is believed that onset time for analgesia can bereached, on the average, about one-fourth to about one-third sooner whena selected narcotic analgesic/caffeine composition of the invention isused rather than when the narcotic analgesic alone is employed. Also,approximately one-fifth to one-third less of the selected narcoticanalgesic can be used in the caffeine combination to achieve the sameanalgesic effect as that obtained by use of the narcotic analgesicalone; in other words, the addition of caffeine decreases the amount ofthe selected narcotic analgesic to two-thirds to four-fifths of theusual amount to achieve the same effect. These ratios may vary, however,depending on the patient's individual response, the selected dosagelevel of the active ingredients etc.

The selected narcotic analgesic/caffeine compositions of the presentinvention are also advantageous in that the use of caffeine counteractsthe sedative effects of the selected narcotic analgesic such that thepatient is more alert, has better motor skills and may have an improvedsense of well-being as compared to when the narcotic analgesic isadministered alone.

The precise amount of selected narcotic analgesic for use in the presentnarcotic analgesic/caffeine compositions will vary depending, forexample, on the specific drug chosen, the size and kind of the mammaland the condition for which the drug is administered. Generallyspeaking, the selected narcotic analgesic can be employed in any amountknown to be an orally effective analgesic amount as well as at dosesabout one-fifth to one-third lower than the usual amounts.

For humans, typical effective analgesic amounts of presently preferrednarcotics for use in unit dose narcotic analgesic/caffeine compositionsof the present invention, to be administered every 4 to 6 hours asneeded, are about 1 to 5 mg hydromorphone hydrochloride, about 15 to 60mg codeine sulfate or phosphate, about 2.5 to 5 mg oxycodonehydrochloride or a mixture of oxycodone hydrochloride and oxycodoneterephthalate (e.g. 4.50 mg oxycodone hydrochloride+0.38 mg oxycodoneterephthalate, or 2.25 mg oxycodone hydrochloride+0.19 mg oxycodoneterephthalate), about 1 to 3 mg levorphanol tartrate, about 50 mgmeperidine hydrochloride, about 65 mg propoxyphene hydrochloride, about100 mg propoxyphene napsylate, about 5 to 10 mg methadone hydrochloride,about 25 to 60 mg propiram fumarate, about 8 to 10 mg buprenorphinehydrochloride, about 25 to 50 mg pentazocine hydrochloride, about 10 to30 mg nalbuphine hydrochloride, about 4 to 8 mg butorphanol tartrate orabout 100 to 500 mg meptazinol hydrochloride. The amount of caffeine inthe analgesic composition will be an amount sufficient to shorten theonset time and/or to enhance analgesia. For humans, a unit dosageanalgesic composition will typically contain from about 60 to about 200mg (preferably about 65 to 150 mg) caffeine; this dosage level ofcaffeine is generally sufficient to both shorten the onset time andenhance analgesia. The daily analgesic dose in humans will vary with theselected narcotic analgesic, and may of course be as low as the amountcontained in a single unit dose as set forth above. The daily dose foruse in the treatment of moderate to severe pain will preferably notexceed 30 mg hydromorphone hydrochloride, or 360 mg codeine sulfate orphosphate, or 60 mg oxycodone hydrochloride orhydrochloride/terephthalate mixture, or 18 mg levorphanol tartrate, or600 mg meperidine hydrochloride, or 390 mg propoxyphene hydrochloride,or 600 mg propoxyphene napsylate, or 60 mg methadone hydrochloride, or300 mg propiram fumarate, or 60 mg buprenorphine hydrochloride, or 300mg pentazocine hydrochloride, or 180 mg nalbuphine hydrochloride, or 48mg butorphanol tartrate, or 3000 mg meptazinol hydrochloride, and 1000mg caffeine, although greater amounts could be employed if tolerated bythe patient.

When a selected NSAID and a selected narcotic analgesic as definedherein are combined, enhanced analgesia results; at a given dosagelevel, the analgesic effect of the combination is greater than foreither the selected NSAID or the selected narcotic analgesic alone.Consequently, it is possible to lower the amount of one of theanalgesics and achieve the same level of analgesia as with a higher doseof that analgesic alone. Generally, it is considered more desirable tolower the dosage of the selected narcotic analgesic, since its sideeffects are considered more undesirable than those of the selectedNSAID. The lowering of dosage of the selected narcotic analgesic leadsto lower incidence and less severity of its attendant side effects, andless likelihood of addiction potential. Generally speaking, the additionof a selected NSAID can be expected to decrease the amount of theselected narcotic analgesic needed to two-thirds to four-fifths of theusual amount to achieve the same effect. These ratios may vary, however,depending on the particular drugs selected, the patient's individualresponse, and the selected dosage levels of the active ingredients.Moreover, it is possible to maintain the usual amount of the selectednarcotic analgesic and take advantage of the enhanced analgesicresponse. When a selected narcotic analgesic and a selected NSAID arefurther combined with caffeine in accord with the present invention, thecombination has all of the unexpected results (hastened onset, etc.) andhas all of the advantages discussed in detail above for the selectednarcotic analgesic/caffeine combination. Moreover, the selected narcoticanalgesic/selected NSAID/caffeine combination shares the enhancement ofanalgesia made possible by the combination of the two different kinds ofanalgesics. Since the presence of caffeine counteracts the sedativeproperties of the narcotic, the resultant composition is especially ofinterest as a daytime oral analgesic, effective against severe pain,which can be utilized in patients who must remain alert and active.

It is believed that caffeine enhances the analgesic effect not only ofthe selected narcotic analgesic but also of the selected NSAID in thethree-component combination; and that caffeine enhances the onset ofanalgesia from both of these drugs. This is likely to produce a strongeranalgesic response than that produced, not only by the selected narcoticanalgesic alone or the selected NSAID alone, but also by the selectedNSAID/caffeine, selected narcotic analgesic/caffeine and selectednarcotic analgesic/selected NSAID combinations. Nevertheless, it is notgenerally recommended that the amounts of selected narcotic analgesicand selected NSAID in the composition with caffeine be further reducedfrom those utilized in the selected narcotic analgesic/selected NSAIDcombination; rather, the three-component composition is intended to takeadvantage of the further enhanced and quicker analgesia provided by thepresence of caffeine. Thus, for use in treating humans, theanalgesically effective amount of selected narcotic analgesic in a unitdose three-component composition will typically be as set forthhereinabove for the two-component narcotic analgesic/caffeinecompositions of the invention. The amount of selected NSAID in a unitdose three-component composition will be an amount sufficient to enhanceanalgesia. For humans, a unit dosage three-component composition willtypically contain an amount of selected NSAID which is well toleratedalone when used to treat mild to moderate pain and which is sufficientto enhance analgesia when combined with the selected narcotic analgesic;such amounts are the same as those set forth hereinabove as effectiveanalgesic amounts in the discussion of the selected NSAID/caffeinetwo-component compositions. The amount of caffeine in thethree-component composition will be an amount sufficient to furtherenhance analgesia or to hasten its onset; in humans, this amount willtypically be from about 60 to about 200 mg (preferably 65 to 150 mg), anamount generally sufficient to both hasten onset and enhance analgesia.The daily analgesic dose in humans for each analgesic in thethree-component composition will generally not exceed their dailyanalgesic doses as disclosed hereinabove in connection with thetwo-component mixtures, while the daily dosage of caffeine again willgenerally not exceed 1000 mg. Of course, greater amounts can be used iftolerated by the patient.

The presently preferred narcotics described hereinabove for use in thenarcotic analgesic/caffeine compositions are likewise preferred for usein the three-component compositions. As these preferred narcotics aretypically administered every 4 to 6 hours, particularly preferred NSAIDsfor use in the three-component compositions will be selected from amongthose preferred NSAIDs described hereinabove for use in theNSAID/caffeine compositions but which are likewise effective for 4 to 6hour periods (zomepirac sodium, ketoprofen, ibuprofen, flurbiprofen,fenoprofen, mefenamic acid and the like). If a longer acting narcoticanalgesic is employed, or if the selected narcotic analgesic isformulated in sustained release form, then one of the longer acting ofthe NSAIDs could be combined therewith and, if desired, additionalcaffeine could be included in sustained release form. Alternatively, allthree components might be formulated for sustained release, in whichcase much larger amounts of each would be incorporated in an individualunit.

While the compositions of the invention are preferably for oral use,they may also be formulated for and administered by other methods whichare known for administering analgesics, e.g. as suppositories. Also, thepreferred human dosage levels indicated above are for use in adults;pediatric compositions would contain proportionately less of the activeingredients.

The compositions of the present invention are very convenientlyadministered to mammals by any route of administration suitable for theselected NSAID and/or selected narcotic analgesic component, e.g. oralor rectal. Preferably, the combination is formulated with any suitablenontoxic pharmaceutically acceptable inert carrier material. Suchcarrier materials are well known to those skilled in the art ofpharmaceutical formulations. For those not skilled in the art, referenceis made to the text entitled, "REMINGTON'S PHARMACEUTICAL SCIENCES"(Fourteenth Edition), 1970. In a typical preparation for oraladministration, e.g., tablet or capsule, the selected NSAID in aneffective analgesic or anti-inflammatory amount and caffeine in anamount sufficient to enhance the analgesic or anti-inflammatory responseor to hasten its onset, or the selected narcotic analgesic in aneffective analgesic amount and caffeine in an amount sufficient toenhance the analgesic response or to hasten its onset, or the selectednarcotic analgesic in an effective analgesic amount together with aselected NSAID in an amount sufficient to enhance the analgesic responseand caffeine in an amount sufficient to further enhance the analgesicresponse or to hasten its onset, are combined with any oral nontoxicpharmaceutically acceptable inert carrier such as lactose, starch(pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin,mannitol and powdered sugar. Additionally, when required, suitablebinders, lubricants, disintegrating agents and coloring agents can alsobe included. Typical binders include starch, gelatin, sugars such assucrose, molasses and lactose, natural and synthetic gums such asacacia, sodium alignate, extract of Irish moss, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, polyethylene glycol,ethylcellulose and waxes. Typical lubricants for use in these dosageforms can include, without limitation, boric acid, sodium benzoate,sodium acetate, sodium chloride, leucine and polyethylene glycol.Suitable disintegrators can include, without limitation, starch,methylcellulose, agar, bentonite, cellulose, wood products, alginicacid, guar gum, citris pulp, carboxymethylcellulose and sodium laurylsulfate. If desired, a conventional pharmaceutically acceptable dye canbe incorporated into the dosage unit form, i.e., any of the standardFD&C dyes. Sweetening and flavoring agents and preservatives can also beincluded, particularly when a liquid dosage form is formulated, e.g. anelixir, suspension or syrup. Also, when the dosage form is a capusle, itmay contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. Such compositions should preferably contain at least 0.1%of active components; generally, the active ingredients will be betweenabout 2% to about 60% of the weight of the unit.

Illustrative of typical unit dosage forms are tablets or capsulescontaining the amounts indicated in the table below. Note that theasterisk (*) indicates that the adjacent amount is in sustained releaseform, e.g. "130 mg+130 mg*" means that the first 130 mg is formulatedfor immediate release, while the second 130 mg is in sustained releaseform.

                  TABLE                                                           ______________________________________                                        Selected Narcotic                                                             Analgesic    Selected NSAID                                                                              Caffeine                                           ______________________________________                                                     diflunisal,                                                                   125 mg        130 mg + 130 mg*                                                250 mg        130 mg + 130 mg*                                                500 mg        130 mg + 130 mg*                                                mg sodium,                                                                     25 mg          or 130 mg                                                      50 mg        65 or 130 mg                                                    100 mg        65 or 130 mg                                                    ibuprofen,                                                                     50 mg        65 or 130 mg                                                    100 mg        65 or 130 mg                                                    200 mg        65 or 130 mg                                                    300 mg        65 or 130 mg                                                    400 mg        65 or 130 mg                                                    500 mg        65 or 130 mg                                                    600 mg        65 or 130 mg                                                    naproxen,                                                                     125 mg        130 mg + 130 mg*                                                250 mg        130 mg + 130 mg*                                                250 mg        65 mg + 65 mg*                                                  500 mg        130 mg + 130 mg*                                                flurbiprofen,                                                                  25 mg        130 mg                                                           50 mg        130 mg                                                          fenoprofen,                                                                    50 mg        65 or 130 mg                                                    100 mg        130 mg                                                          200 mg        65 or 130 mg                                                    300 mg        130 mg                                                          600 mg        130 mg                                                          piroxicam,                                                                     10 mg        130 mg + 130 mg*                                                 20 mg        130 mg + 130 mg*                                                 20 mg        130 mg                                                           20 mg        130 mg + 260 mg*                                                tolmetin sodium,                                                              200 mg        130 mg                                                          400 mg        130 mg                                                          ibuprofen                                                                     aluminum,                                                                     400 mg        130 mg                                                          mefenamic acid,                                                               125 mg        65 or 130 mg                                                    250 mg        65 or 130 mg                                                    indomethacin,                                                                  25 mg        130 mg                                                           50 mg        130 mg                                                          ketoprofen,                                                                    25 mg        65 or 130 mg                                                     50 mg        65 or 130 mg                                                    fenbufen,                                                                     200 mg        65 or 130 mg                                                    400 mg        65 or 130 mg                                                    800 mg        65 or 130 mg                                                    sulindac,                                                                     150 mg        130 mg + 130 mg*                                                200 mg        130 mg + 130 mg*                                                meclofenamate                                                                 sodium,                                                                        50 mg        65 or 130 mg                                       hydromorphone                                                                 hydrochloride,                                                                 1 mg                      130 mg                                              2 mg                      130 mg                                              3 mg                      130 mg                                              4 mg                      130 mg                                              5 mg                      130 mg                                             codeine sulfate or                                                            phosphate,                                                                     15 mg                     130 mg                                              30 mg                     130 mg                                              45 mg                     130 mg                                              60 mg                     130 mg                                             oxycodone                                                                     hydrochloride,                                                                2.5 mg                     130 mg                                              5 mg                      130 mg                                             meptazinol                                                                    hydrochloride,                                                                200 mg                     65 or 130 mg                                       oxycodone                                                                     hydrochloride/                                                                terephthalate mixture,                                                         4.5 mg/0.38 mg            130 mg                                             2.25 mg/0.19 mg            130 mg                                             levorphanol tartrate,                                                          1 mg                      130 mg                                              2 mg                      130 mg                                              3 mg                      130 mg                                             meperidine                                                                    hydrochloride,                                                                 50 mg                     130 mg                                             propoxyphene                                                                  hydrochloride,                                                                 65 mg                     130 mg                                             propoxyphene                                                                  napsylate,                                                                    100 mg                     130 mg                                             methadone                                                                     hydrochloride,                                                                 5 mg                      130 mg                                              10 mg                     130 mg                                             propiram fumarate                                                              35 mg                     65 or 130 mg                                        50 mg                     130 mg                                             buprenorphine                                                                 hydrochloride,                                                                 8 mg                      130 mg                                              10 mg                     130 mg                                             pentazocine                                                                   hydrochloride,                                                                 25 mg                     65 or 130 mg                                        50 mg                     130 mg                                             nalbuphine                                                                    hydrochloride,                                                                 10 mg                     130 mg                                              15 mg                     65 or 130 mg                                        30 mg                     130 mg                                             butorphanol tartrate,                                                          4 mg                      130 mg                                              8 mg                      65 or 130 mg                                       nalbuphine                                                                    hydrochloride,                                                                             ibuprofen,                                                        15 mg       200 or 400 mg 130 mg                                             propiram fumarate,                                                                         ibuprofen,                                                        35 mg       200 or 400 mg 130 mg                                              50 mg       200 or 400 mg 130 mg                                              35 mg       200 or 400 mg  65 mg                                              50 mg       200 or 400 mg  65 mg                                             pentazocine                                                                   hydrochloride,                                                                             ibuprofen,                                                        25 mg       200 or 400 mg 130 mg                                             butorphanol tartrate,                                                                      ibuprofen,                                                        8 mg        400 mg        130 mg                                             propiram fumarate,                                                                         zomepirac sodium,                                                 50 mg       50 or 100 mg  130 mg                                              35 mg       50 or 100 mg  130 mg                                             propoxyphene                                                                  hydrochloride,                                                                             fenoprofen,                                                       65 mg       200 mg        130 mg                                             propoxyphene                                                                  napsylate,   fenoprofen,                                                      100 mg       200 mg        130 mg                                             propiram fumarate,                                                                         fenbufen,                                                        35 or 50 mg  400 mg        130 mg                                             35 or 50 mg  800 mg        130 mg                                             35 or 50 mg  400 mg         65 mg                                             propiram fumarate,                                                                         mefenamic acid,                                                   35 mg       250 mg        130 mg                                             codeine sulfate or                                                            phosphate,   mefenamic acid,                                                   30 mg       250 mg        130 mg                                              30 mg       125 mg        130 mg                                             propiram fumarate,                                                                         ketoprofen,                                                       35 mg       25 or 50 mg   130 mg                                             meptazinol                                                                    hydrochloride,                                                                             ketoprofen,                                                      200 mg       25 or 50 mg   130 mg                                             200 mg       25 or 50 mg    65 mg                                             ______________________________________                                    

If desired, compositions of the present invention may be formulated forparenteral use by known methods. The two-component selected narcoticanalgesic/caffeine composition is of particular value in the case ofpatients suffering severe pain who cannot tolerate such medicationadministered orally.

It is also possible to formulate the oral compositions of the inventionin such a manner that the possibility that the narcotic analgesic couldbe extracted therefrom and then abused parenterally will besignificantly reduced. This may be accomplished by combining the drugswith insoluble excipients such as methylcellulose to form a dosage formthat is insoluble in water. Such water-insoluble oral dosage forms arealready known for at least some of the narcotics themselves, e.g. forpropiram fumarate and methadone hydrochloride.

The analgesic and anti-inflammatory effects of the compositions of thepresent invention can be quantitatively evaluated in animals in thetests described below:

Antiphenylquinone Writhing Test

This test is a standard procedure for detecting and comparing analgesicactivity and generally correlates well with human efficacy.

Mice are first dosed with the medications studied. The medications usedare two dose levels of a selected NSAID with and without caffeine, or ofa selected narcotic analgesic with and without caffeine, or of aselected narcotic analgesic+a selected NSAID with and without caffeine.The mice are then challenged with phenyl-p-benzoquinone givenintraperitoneally and observed for the characteristic stretch-writhingsyndrome. Lack of writhing constitutes a positive response. The degreeof analgesic protection can be calculated on the basis of suppression ofwrithing relative to control animals run the same day. Time responsedata are also obtained. The test is a modification from the methods ofSigmund et al and Blumberg et al (Sigmund, E., Cadmus, R., and Lu, G.,Proc. Soc. Exp. Biol. and Med. 95, 729-731, 1957; Blumberg, H. et al,Proc Soc. Exp. Biol. Med. 118, 763-766, 1965).

The Inflamed Rat Paw Test

Pressure Induced Stimuli

The method of Randall-Selitto, modified according to Winter et al isused to ascertain the escape response threshold resulting from theapplication of increasing pressure to the yeast inflamed left hind paw.Drug treatment is given. The medications studied are two dose levels ofa selected NSAID with and without caffeine. A constantly increasingforce is applied to the paw and the "flight reaction" is observed andrecorded (Randall, L. Q., and Selitto, J. J.: Arch. Int. Pharmacodyn.,II, 409-419, 1957; Winter, C. A., and Lars, F.: J. Pharmacol. Exp.Therap., 148, 373-379, 1965).

The Mouse Tail-flick Test

Tail-flick testing in mice is modified after D'Amour and Smith, usingcontrolled high intensity heat applied to the tail. Normal anddrug-treated mice are observed and the reaction time is measured. Thedrugs used are two doses of a selected narcotic analgesic with andwithout caffeine. (D'Amour, E., and Smith, L., J. Pharmacol., 72, 74-79,1941).

Haffner Tail-Pinch Method

A modification of the procedure of Haffner is used to ascertain drugeffects on the aggressive attacking responses elicited by a pressurestimulus pinching the tail of a rat. A clamp is on the base of eachrat's tail prior to drug treatment and again at specified intervalsafter treatment. The time required to elicit clear attacking and bitingbehavior directed towards the stimulus is observed. The medicationsstuided are two doses of a selected narcotic analgesic with and withoutcaffeine. (Haffner, F.: Experimentelle Prufung Schmerzstillender Mittel.Deutsch med. Wschr., 55, 731-732, 1929).

Mouse Hot-Plate Test (Thermal Stimuli)

A modification of the method of Woolfe and MacDonald is used andinvolves the application of a controlled heat stimulus to the paws ofmice. Drug is administered to the treatment group. The latency betweenthe time of the animal's contact with the hot-plate and the observationof the standard pain response, jumping and/or rapid patting of one orboth hind paws is measured. The medications studied are two doses of aselected narcotic analgesic with and without caffeine. (Woolfe, G., andMacDonald, A. D.: J. Pharmacol. Exp. Ther., 80, 300-307, 1944).

Adjuvant Arthritis Test

Adjuvant arthritis in the rat is a widely used model for humanrheumatoid arthritis. It is basically an immunological reaction,involving a cellular immune response to an injected bacterial adjuvant.The response is systemic, but develops mainly in the limbs as apolyarthritis. The degree of arthritis in the hind legs is assessedeither visually or by measuring the foot volume of the 21st day afterinjection of the adjuvant.

A single subcutaneous injection of 1 mg Mycobacterium butyricumsuspended in 0.1 ml mineral oil is injected into the right hindpaws ofrats. The swelling of the injected hind leg measured on day 16constitutes the secondary response. Drugs are administered p.o. daily,beginning 1 day prior to injection of adjuvant. The medications used aretwo dose levels of selected NSAID with and without caffeine. Results areexpressed as percent suppression of the control. [Walz, D. T., DiMartino, M. J., and Misher, A.: Ann. Rheum. Dis., 30, 303-306 (1971)].

To establish the efficacy of the compositions of this invention inhumans, patients with moderate to severe pain requiring an oralanalgesic can be administered a selected narcotic analgesic or NSAIDwith and without caffeine or a selected narcotic analgesic+a selectedNSAID with and without caffeine, while patients suffering frominflammatory or degenerative joint disease, e.g., rheumatoid arthritis,osteoarthritis, gout or acute musculo-skeletal disease requiring an oralanti-inflammatory agent, can be administered a selected NSAID with andwithout caffeine. To determine analgesic efficacy, a nurse observerinterviews the patients as to their level of pain or stiffness andswelling at subsequent periods of time. Patients are asked tosubjectively estimate the time at which the medication begins to providerelief. Appropriate statistical methods can be used to show that on theaverage the compositions with caffeine have shorter onset and are moreefficacious. (Laska, E., Gormely, M., Sunshine, A., Belleville, J. W.,Kantor, T., Forrest, W. H., Siegel, C., and Meisner, M.: "A BioassayComputer Program for Analgesic Clinical Trials", Clin. Pharmacol. Ther.8: 658, 1967; Cox, D. R., "Regression Models and Life Tables", JournalRoyal Statistical Society, Series B, Volume 34: 187-202, 1972).Evaluation of efficacy in inflammatory and degenerative joint disease isaccomplished by patient's self-assessment of severity of pain, durationof morning stiffness, general feeling, and ease of movement; and byphysician's evaluation of objective measures such as tenderness,swelling, number of painful joints, plus various tests of function suchas grip strength, speed of walking, chest expansion and finger to floor.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the instant invention,and without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be, within thefull range of equivalence of the following claims.

What we claim is:
 1. A method for eliciting an onset hastened andenhanced analgesic or anti-inflammatory response in a mammal, comprisingadministering to said mammal a pharmaceutical composition comprising:(a)an analgesically and anti-inflammatorily effective amount of anon-steroidal anti-inflammatory drug comprising an acetic acidderivative or a pharmaceutically acceptable salt thereof selected fromtolmetin and indomethacin; and (b) an amount of caffeine sufficient tohasten the onset of and enhance the analgesic or anti-inflammatoryresponse.
 2. A method according to claim 1, wherein the non-steroidalanti-inflammatory drug is tolmetin.
 3. A method according to claim 1,wherein the non-steroidal anti-inflammatory drug is indomethacin.
 4. Amethod according to claim 1, comprising from about 60 mg and about 200mg caffeine.
 5. A method according to claim 4, comprising from about 65mg to about 150 mg caffeine.
 6. A method according to claim 1,comprising from about 25 mg to about 400 mg of said acetic acidderivative or pharmaceutically salt thereof and from about 60 mg toabout 200 mg caffeine.
 7. A method according to claim 2, comprising fromabout 200 mg to about 400 mg tolmetin or pharmaceutically acceptablesalt thereof and from about 60 mg to about 200 mg caffeine.
 8. A methodaccording to claim 3, comprising from about 25 mg to about 50 mgindomethacin or pharmaceutically acceptable salt thereof and from about60 mg to about 200 mg caffeine.
 9. A method according to claim 2,wherein said tolmetin or pharmaceutically acceptable salt thereof istolmetin sodium.
 10. A pharmaceutical composition of matter for use ineliciting an onset hastened or enhanced analgesic or anti-inflammatoryresponse in a mammal, said composition comprising:(a) an analgesicallyand anti-inflammatorily effective amount of a non-steroidalanti-inflammatory drug comprising an acetic acid derivative orpharmaceutically acceptable salt thereof selected from tolmetin andindomethacin; and (b) an amount of caffeine sufficient to hasten theonset of and enhance the analgesic or anti-inflammatory response.
 11. Apharmaceutical composition according to claim 10, wherein thenon-steroidal anti-inflammatory drug is tolmetin.
 12. A pharmaceuticalcomposition according to claim 10, wherein the non-steroidalanti-inflammatory drug is indomethacin.
 13. A pharmaceutical compositionaccording to claim 10, comprising from about 60 mg to about 200 mgcaffeine.
 14. A pharmaceutical composition according to claim 13,comprising about 65 mg to about 150 mg caffeine.
 15. A pharmaceuticalcomposition according to claim 10, comprising from about 25 mg to about400 mg of said acetic acid derivative or pharmaceutically acceptablesalt thereof and from about 60 mg to about 200 mg. caffeine.
 16. Apharmaceutical composition according to claim 11, comprising from about200 mg to about 400 mg tolmetin or pharmaceutically acceptable saltthereof and from about 60 mg to about 200 mg caffeine.
 17. Apharmaceutical composition according to claim 12, comprising from about25 mg to about 50 mg indomethacin or pharmaceutically acceptable saltthereof and from 60 mg to about 200 mg caffeine.
 18. A pharmaceuticalcomposition according to claim 11, wherein said tolmetin orpharmaceutically acceptable salt thereof is tolmetin sodium.
 19. Apharmaceutical composition according to claim 10, further comprising apharmaceutically acceptable inert carrier.
 20. A pharmaceuticalcomposition according to claim 19, said composition being adapted fororal administration.
 21. A pharmaceutical composition according to claim20, said composition being formulated as a tablet or capsule.
 22. Apharmaceutical composition according to claim 19, wherein saidcomposition is in sustained release form.
 23. A pharmaceuticalcomposition according to claim 19, said composition being adapted forrectal administration.
 24. A pharmaceutical composition according toclaim 23, said composition being formulated as a suppository.